The ability of analog compounds to bind to localized ligands within the body would make it possible, in principle, to utilize such compounds for in situ imaging of the ligands by PET, SPECT and similar imaging methods. In principle, nothing need be known about the nature of the ligand, as long as binding occurs, and such binding is specific for a class of cells, organs, tissues or receptors of interest. PET imaging is accomplished with the aid of tracer compounds labeled with a positron-emitting isotope (Goodman, M. M. Clinical Positron Emission Tomography, Mosby Yearbook, 1992, K. F. Hubner et al., Chapter 14). For most biological materials, suitable isotopes are few. The carbon isotope, .sup.11 C!, has been used for PET, but its short half-life of 20.5 minutes limits its usefulness to compounds that can be synthesized and purified quickly, and to facilities that are proximate to a cyclotron where the precursor .sup.11 C! starting material is generated. Other isotopes have even shorter half-lives. .sup.13 N! has a half-life of 10 minutes and .sup.15 O! has an even shorter half-life of 2 minutes. The emissions of both are more energetic than those of .sup.11 C!. Nevertheless, PET studies have been carried out with these isotopes (Hubner, K. F., in Clinical Positron Emission Tomography, Mosby Year Book, 1992, K. F. Hubner, et al., Chapter 2). A more useful isotope, .sup.18 F!, has a half-life of 110 minutes. This allows sufficient time for incorporation into a radio-labeled tracer, for purification and for administration into a human or animal subject. In addition, facilities more remote from a cyclotron, up to about a 200 mile radius, can make use of .sup.18 F! labeled compounds. Disadvantages of .sup.18 F! are the relative scarcity of fluorinated analogs that have functional equivalence to naturally-occurring biological materials, and the difficulty of designing methods of synthesis that efficiently utilize the starting material generated in the cyclotron. Such starting material can be either fluoride ion or fluorine gas. In the latter case only one fluorine atom of the bimolecular gas is actually a radionuclide, so the gas is designated .sup.18 F-F. Reactions using .sup.18 F-F as starting material therefore yield products having only one half the radionuclide abundance of reactions utilizing K.sup.18 F as starting material. On the other hand, .sup.8 F! can be prepared in curie quantities as fluoride ion for incorporation into a radiopharmaceutical compound in high specific activity, theoretically 1.7 Ci/nmol using carrier-free nucleophilic substitution reactions. The energy emission of .sup.8 F! is 0.635 MeV, resulting in a relatively short, 2.4 mm average positron range in tissue, permitting high resolution PET images.
SPECT imaging employs isotope tracers that emit high energy photons (.gamma.-emitters). The range of useful isotopes is greater than for PET, but SPECT provides lower three-dimensional resolution. Nevertheless, SPECT is widely used to obtain clinically significant information about analog binding, localization and clearance rates. A useful isotope for SPECT imaging is .sup.123 I!, a .gamma.-emitter with a 13.3 hour half life. Compounds labeled with .sup.123 I! can be shipped up to about 1000 miles from the manufacturing site, or the isotope itself can be transported for on-site synthesis. Eighty-five percent of the isotope's emissions are 159 KeV photons, which is readily measured by SPECT instrumentation currently in use.
Use of .sup.18 F! labeled compounds in PET has been limited to a few analog compounds. Most notably, .sup.18 F!-fluorodeoxyglucose has been widely used in studies of glucose metabolism and localization of glucose uptake associated with brain activity. .sup.8 F!-L-fluorodopa and other dopamine receptor analogs have also been used in mapping dopamine receptor distribution.
Other halogen isotopes can serve for PET or SPECT imaging, or for conventional tracer labeling. These include .sup.75 Br, .sup.76 Br, .sup.77 Br and .sup.82 Br as having usable half-lives and emission characteristics. In general, the chemical means exist to substitute any halogen moiety for the described isotopes. Therefore, the biochemical or physiological activities of any halogenated homolog of the described compounds are now available for use by those skilled in the art, including stable isotope halogen homologs.
Currently, there does not exist a single radiopharmaceutical that can be labeled with either fluorine-18, bromine-76 or iodine-123 amenable for regional distribution that is efficacious in differentiating major depression from other psychiatric disorders. Citalopram (Hume, S. P. et al., Nucl. Med. Biol. (1991) 18:339-351), paroxetine (Suehiro, M. et al., Nucl. Med. Biol. (1991) 18:791-796), fluoxetine (Kilbourn, M. R. et al., J. Label Compound Radiopharm. (1989) 26:412-414), and nitroquipazine (Mathis, C. et al., J. Nucl. Med., (1993) 34:7P-8P), potent serotonin transporter ligands, have been radiolabeled with carbon-11 and fluorine-18 as potential radiotracers for imaging and quantifying serotonin transporter sites in the brain using PET. Unfortunately, the in vivo affinity and selectivity for the serotonin transporter of these radiolabeled ligands did not reflect their in vitro potencies which resulted in poor quality images of brain regions rich in serotonergic neurons. Recently, a series of antidepressants, trans-1,2,3,5,6,10b-hexahydro-pyrrolo2,1-a!isoquinoline derivatives have been found to be potent inhibitors with low and subnanomolar affinity for the serotonin transporter (Maryanoff, B. E. et al., J. Med. Chem. (1987) 30:1433-1454). The most potent inhibitor of the series, trans-1,2,3,5,6,10b-hexahydro-6-4-(methylthio)phenyl!pyrrolo 2,1-a!isoquinoline (McN-5652Z) (Ki=0.68 nM vs. 100-200 nM .sup.3 H!serotonin), has been labeled with carbon-11 as a PET radioligand for mapping serotonin transporter sites (Suehiro, M. et al., J. Nucl. Med. (1993) 31:841-848). Carbon-11 McN-5652Z showed the greatest accumulation in brain regions rich in serotonergic neurons with greater cortex to cerebellum ratios (4.3 to 1) than previously tested PET serotonin transporter ligands (Suehiro, M. et al., J. Nucl. Med. (1993) 34:120-127). However, the very short 20 minute half-life of carbon-11 minute half-life may not allow ample time for measuring the entry and longitudinal selective regional uptake of the radioligand and analysis of the presence of radiolabeled metabolites which is crucial in receptor imaging and tracer kinetic modeling. thus, there still exists a need for a greater than 20 minute half-life radiolabeled probe that demonstrates sub to low nanomolar affinity, high selectivity, and a low dissociation rate from the molecular serotonin transporter binding site. Because the serotonin transporter plays a pivotal role in serotonin neurotransmission, the development of radiopharmaceuticals radiolabeled with gamma emitting isotopes which exhibit pronounced brain uptake, very high selectivity and affinity for the transporter, and low non-specific binding would be excellent for the measurement of the density of presynaptic serotonin transporter sites by emission tomography.
French patent of addition 81/19025, (publication no: 2514353, Apr. 15, 1983) disclosed 4-(2-naphthylmethoxy)-piperidine, (NMP) as having anti-depressant activity. U.S. Pat. No. 4,791,119, Dec. 13, 1988, disclosed administering NMP as an appetite suppressant for treatment of obesity.
U.S. Pat. No. 5,169,855, Dec. 8, 1992, disclosed a series of N-substituted piperidine ethers including 4-(halo-2-naphthalenyl) methoxy!-N-alkyl or aryl piperidines. In general, the described compounds were said to have pharmaceutical utility, agricultural utility or both. Pharmaceutical utility was said to be for treating physiological or drug induced psychosis or dyskinesia.
U.S. Pat. No. 5,296,479 discloses similar N-substituted piperidine ethers having a cycloalkyl group substituted on the piperidine nitrogen. The compounds appear to have sigma receptor binding activity and associated pharmacological effects, however, those compounds tested were poor dopamine receptor binders, compared with haloperidol.
U.S. Pat. No. 5,317,024 discloses other N-substituted piperidine ethers which also have sigma receptor binding activity but lack dopamine receptor binding activity when compared with haloperidol.
The 6-nitroquipazines have been disclosed as having high affinity for serotonin uptake sites in U.S. Pat. No. 5,372,813, Dec. 13, 1994. The possibility of halogen substitution was also disclosed. 6-nitroquipazines labeled with a radioactive halogen, specifically .sup.125l I or .sup.123 I were described by Mathis, C. et al., (1993) J. Nucl. Med. 34:7P-8P and Mathis, C. et al., (1994) J. Label. Cmpds. Radiopharm. 34:905-912. Other articles describing the binding, distribution in brain and in vivo SPECT imaging using a .sup.123 I labeled 6-nitroquipazine have been described by Biegon, A. et al., (1993) Brain Res. 619:236-246 and by Jagust, W. J. et al., (1993) Eur. J. Pharmacol. 242:189-193.
Another substituted piperidine, 4-N-methylpiperidylbenzillate (NMPB) has been disclosed as being a muscarinic acetylcholine receptor antagonist (Mulholland, G. K. et al., (1995) Nucl. Med. Biol. 22:13-17). .sup.11 C-labeled NMPB was used for PET imaging of receptor distribution.